Phase II study of dovitinib in first line metastatic or (nonresectable primary) adrenocortical carcinoma (ACC): SOGUG study 2011-03.

4587 Background: Dovitinib is a novel targeted therapy that inhibits the fribroblast growth factor receptor (FGFR). Preclinical studies have pointed to a major role of this pathway in adrenocortical carcinoma (ACC) thus we aimed to test its clinical efficacy in this tumor. Methods: A phase II proof of concept trial was designed. Since this is an extremely infrequent disease sample size calculation was done taking as a basis the first stage of a two-stage Gehan model. Thus 15 patients needed to be included to show a treatment efficacy of at least 15% (probability of Type I error α = 0.05, power [1 – β] = 0.8). Main inclusion criteria was advanced non-resectable ACC, histologically confirmed, with no prior therapy other than mitotane. Primary endpoint was response rate (RR) by RECIST 1.1 assessed by an independent radiologist. Secondary endpoints included clinical benefit (RR plus stable disease), progression free (PFS) and overall survival (OS). Dovitinib was administered at 500mg daily dose 5 days on 2 days off for 6 months. Continuation of therapy was permitted at physician criteria. Results: From January 2012 to August 2012, 17 patients (5 male and 12 female) have been included in 7 institutions. Median age was 53 years (range 26-72); ECOG was 0-1 in 15 patients, 2 in one patient and N/A in one patient. 77 cycles, defined as one month on treatment, have been administered with dose reductions in 6 (7.8%). Grade 3-4 adverse events deemed as related to the drug were: rash (6%), asthenia (12%), diarrhea (6%), GGT elevation (18%), nausea (6%), hypertriglyceridemia (6%), hypertension (6%), hyperkalemia (6%). 13 patients withdrew treatment because of disease progression and 4 remain on dovitinib. No toxic death was reported. After a median follow-up of 5, 2 months (range 2,27 – 9,7) no objective response has been observed. Median PFS was 1,8 months (CI 95% [ 1,35 -2,25]), median OS has not been reached and clinical benefit has been achieved in 35% of patients with long lasting stable disease (>6 months) in 23%. Conclusions: Though no objective response was observed, a significant number of long lasting stabilizations have been achieved with an acceptable toxicity. These encouraging results merit further study. Clinical trial information: NCT01514526.

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Phase II study of dovitinib in first-line metastatic or nonresectable primary adrenocortical carcinoma (ACC): SOGUG study 2011-03.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.tps4688 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. TPS4688-TPS4688

Author(s):

Paula Jimenez ◽

Marta Guix ◽

Nuria Lainez Milagro ◽

Luis Leon Mateos ◽

Maria Jose Mendez Vidal ◽

...

Keyword(s):

Phase Ii ◽

Type I Error ◽

Sample Size Calculation ◽

Growth Factor Receptor ◽

Collaborative Group ◽

Type I ◽

Open Label ◽

Prior Therapy ◽

Power Of The Test ◽

Open Label Phase

TPS4688 Background: Dovitinib is a novel targeted therapy, that has proven to inhibit, among other tyrosin kinases, the fibroblast growth factor receptor (FGFR). Since this pathway has been proposed to play a major role in ACC, we aim to test the clinical efficacy of dovitinib in this tumor. Methods: An open label phase II trial has been designed in patients with advanced non-resectable ACC. The objective will be to obtain at least a 15% response rate according to RECIST criteria. Taking as a basis the two-stage Gehan model, 15 patients would need to be included in the first stage to demonstrate a treatment efficacy of at least 15%. Sample size calculation was done based on the following parameters, probability of Type I error α = 0.05, power of the test (1 - β) = 0.8. Main inclusion criteria are advanced non-resectable disease and no prior therapy (other than mitotane). Dovitinib scheduled dose matches currently employed standard in the drug development (500mg daily for 5 days then 2 days off) for 6 months. If clinical benefit is obtained longer treatment will be allowed for particular patients. Since this is an extremely unfrequent disease 7 institutions, members of the SOGUG (Spanish Oncology Genitourinary Group), will participate. The active support of a big collaborative group will guarantee candidate patients to be refereed to such institutions. Starting January 26th 2012 recruitment is scheduled to last around 12 months. A translational research, including whole exome analysis, will be performed in order to improve our scarce knowledge of ACC.

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Erlotinib has activity in androgen-independent prostate cancer (AIPC) patients who are chemotherapy-naive: A phase II trial

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.15606 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 15606-15606 ◽

Cited By ~ 1

Author(s):

C. Nabhan ◽

K. Tolzien ◽

S. Newman ◽

S. Kelby ◽

T. Lestingi ◽

...

Keyword(s):

Disease Progression ◽

Phase Ii ◽

Stable Disease ◽

Clinical Benefit ◽

Single Agent ◽

Growth Factor Receptor ◽

Response Assessment ◽

Complete Response ◽

Clinical Activity ◽

Study Results

15606 Background: Mechanisms of hormone resistance for AIPC are variable. One proposed mechanism is the over expression of the epidermal growth factor receptor (EGFR) which in turn stimulates proliferation through its pathway. We aimed to determine the efficacy of an oral anti-EGFR inhibitor (erlotinib) in this patient population that was chemotherapy-naive. The primary end point was to evaluate the overall clinical benefit defined as the sum of complete response (CR), partial response (PR), and stable disease (SD). Methods: Between January and December 2006, sixteen patients were enrolled onto this phase II study. Median age was 78 years (66–85). Median PSA was 61.9 (9.2–800.2). Median time from initial diagnosis until starting Erlotinib was 7.8 years. Erlotinib was given daily at 150 mg until disease progression. Patients were evaluated every 2 weeks for toxicity. Response assessment took place every 2 cycles (each cycle was 4 weeks). Evaluations included computed tomography of measurable disease areas, bone scans, and serum PSAs. Patients who progressed radiographically but maintained a PSA response or those who progressed biochemically but maintained a radiographic response were considered stable and were allowed to continue on study. Results: Sixteen patients were enrolled with 14 being evaluable at this time (2 patients are early in their course). Median cycles received is 2 (range 1.5–12). One patient achieved a PR and continues on Erlotinib after one year of enrollment. Three patients demonstrated stable disease but two of them later progressed. One patient withdrew after 9 days of starting therapy due to fatigue and poor taste. All other patients developed disease progression after two cycles of therapy. The calculated overall clinical benefit was 28% (4 responses out of 14 patients). One patient died from pneumonia and seizures unrelated to Erlotinib as confirmed by an autopsy that showed progression in the central nervous system. Erlotinib was well-tolerated with skin rash and diarrhea being the most common toxicities. Conclusions: Erlotinib has clinical activity as a single agent in AIPC. Updated results of this ongoing study will be presented at the meeting. Further studies with this agent alone or in combination are warranted. No significant financial relationships to disclose.

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Avelumab and cetuximab in combination with FOLFOX in patients with previously untreated metastatic colorectal cancer (MCRC): The phase II AVETUX-CRC trial (AIO KRK 0216).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.tps3620 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. TPS3620-TPS3620 ◽

Cited By ~ 1

Author(s):

Alexander Stein ◽

Mascha Binder ◽

Carsten Bokemeyer ◽

Salah Eddin Al Batran ◽

Axel Hinke ◽

...

Keyword(s):

Clinical Trial ◽

Mismatch Repair ◽

Phase Ii ◽

Type I Error ◽

Single Agent ◽

Objective Response ◽

Progression Free Survival ◽

Type I ◽

Translational Research Program ◽

Clinical Trial Information

TPS3620 Background: Inhibition of the PD-1/L1 axis has shown to improve survival as single agent in a variety of tumor types. The efficacy of single agent PD-1/L1 inhibition in patients with treatment refractory MCRC seems to be limited to hypermutated tumors characterized by mismatch repair deficiency. 1st line chemotherapy (e.g. FOLFOX) with cetuximab for patients with RAS/BRAF wildtype MCRC result in objective response rates of about 60%, thus substantial antigen release will likely occur triggering immune control. Furthermore, the induction of immunogenic cell death has been recently shown for cetuximab-based regimen. Thus, the evaluation of FOLFOX and cetuximab in combination with avelumab in 1st line MCRC is of particular interest. Methods: AVETUX is a single arm exploratory phase II investigator initiated trial. Patients with RAS/BRAF wildtype MCRC will be included independent of mismatch repair status to receive mFOLFOX6 and cetuximab in combination with avelumab (10mg/kg from day 1 of cycle 2 onwards). Treatment with avelumab is limited to a maximum of 18 months. Primary endpoint is 12month progression-free survival rate, which should be increased from 40% to 57%, with type I error of 10% and 80% power, leading to a sample size of 43 patients. An early stopping rule will be applied in case of an increase in toxicity after the first 15 patients received at least two months of treatment. The trial is flanked by a large translational program including immunoprofiling to determine and correlate the respective immune response signatures with clonal dynamics (RAS/EGFR). Recruitment will start in 11 German sites early 2017. Clinical trial information: EudraCT No 2016-004434-26. Conclusion: The AVETUX trial will determine the feasibility and early efficacy of FOLFOX and cetuximab combined with avelumab in 1st line MCRC. The translational research program will shed light on the potential mode of action of this novel combination. Clinical trial information: 2016-004434-26.

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A phase II multicenter trial of the multitargeted kinase inhibitor sulfatinib in advanced medullary thyroid cancer (MTC) and radioiodine (RAI)-refractory differentiated thyroid cancer (DTC).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.6037 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 6037-6037 ◽

Cited By ~ 3

Author(s):

Jiaying Chen ◽

Qinghai Ji ◽

Junning Cao ◽

Dongmei Ji ◽

Chunmei Bai ◽

...

Keyword(s):

Thyroid Cancer ◽

Growth Factor ◽

Disease Progression ◽

Phase Ii ◽

Kinase Inhibitor ◽

Phase Ii Study ◽

Objective Response ◽

Growth Factor Receptor ◽

Stage I ◽

Grade 3

6037 Background: Sulfatinib is an oral tyrosine kinase inhibitor targeting Vascular Endothelial Growth Factor Receptor (VEGFR), Fibroblast Growth Factor Receptor 1 (FGFR 1), and Colony Stimulating Factor 1 Receptor (CSF1R). In a proof of concept (PoC) phase II study, sulfatinib showed promising efficacy in patients (pts) with neuroendocrine tumors (NETs). Methods: This is an open label, two cohorts phase II study using Simon's two-stage design. In stage I, 15 pts will be enrolled in each cohort (advanced MTC or iodine-refractory DTC), and 10 more pts will be enrolled in a cohort in stage II if at least 2 PR observed in that cohort in stage I. Pts are required to have progressive disease in the past 12 months, but could not have received > 1 prior anti-angiogenesis therapy. Pts are treated with oral sulfatinib 300 mg once daily until disease progression, death, or intolerable toxicity. Primary endpoint is Objective Response Rate (ORR) by investigator per RECIST 1.1. Results: As of Dec 31 2016,the studyenrolled 18 pts (MTC: 6, DTC: 12), amongst whom 17 pts were efficacy evaluable. There were a total of 4 confirmed PRs, 1 in the MTC cohort and 3 in the DTC cohort, respectively. The others best response was stable disease (SD). 11 pts (61.1%) had dose interruption due to adverse events (AEs) and 5 pts (27.8%) had dose reduction. Two pts discontinued therapy (1 patient due to disease progression, another due to subject's decision). The most commonly reported AEs were proteinuria 72.2% (Grade 3-4: 22.2%), hypertriglyceridemia 50.0% (Grade 3-4: 0%), hypertension 44.4% (Grade 3-4: 16.7%), blood bilirubin increased 44.4% (Grade 3-4: 5.6%), and diarrhea 33.3% (Grade 3-4: 0%). No Grade 5 AE was reported by the time of data cut-off. Conclusions: Sulfatinib appears to be well tolerated in the pts with advanced MTC and RAI refractory DTC. Safety profile seems to be consistent to previous report, with mostly manageable AEs. Efficacy is encouraging in both indications. Further investigation is warranted. Clinical trial information: NCT02614495.

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Phase II study of the farnesyl transferase inhibitor tipifarnib plus fulvestrant in postmenopausal patients with hormone receptor-positive breast cancer: New York Cancer Consortium Trial P6205

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.1037 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 1037-1037 ◽

Cited By ~ 1

Author(s):

T. Li ◽

P. Christos ◽

J. A. Sparano ◽

D. L. Hershman ◽

K. O’Brien ◽

...

Keyword(s):

Breast Cancer ◽

Stable Disease ◽

Clinical Benefit ◽

Hormone Receptor ◽

Single Agent ◽

Objective Response ◽

Breast Cancer Cell Lines ◽

Type I ◽

Resistant Disease ◽

Hormone Receptor Positive

1037 Background: Tipifarnib and fulvestrant both have single agent activity in hormone receptor-positive (HR+) metastatic breast cancer (MBC), and tipifarnib enhances the activity of anti-estrogens in HR+ breast cancer cell lines. Methods: Eligibility criteria: measurable HR+ MBC, postmenopausal status, ECOG PS of 0–2, and no prior chemotherapy for MBC. Treatment: fulvestrant 250 mg IM on day 1 plus oral tipifarnib 300 mg BID on days 1–21 every 28 days (defined as one cycle). Response was evaluated by RECIST criteria every 3 cycles. The study was suspended for efficacy/futility analysis after 33 of 46 patients were accrued. It was designed to detect an improvement in clinical benefit rate (CBR; defined as objective response or stable disease for at least 24 weeks) from 50% to 70% (90% power, type I error 10%), and would require at least 26 of 42 eligible/evaluable patients to have clinical benefit (CB). The expected CBR for fulvestrant alone is 30% in aromatase inhibitor (AI) resistant disease (Ingle, 2006), 45% in tamoxifen (tam)-resistant disease (Osborne, 2002), and 60% when used as first line endocrine therapy (ET) (Howell, 2004). Results: Of 33 patients enrolled, 28 are currently assessable for CBR (2 were ineligible, and 3 have stable disease for < 6 months and remain on treatment). Grade 3/4 toxicity: neutropenia (15%), pain (11%) and gastrointestinal toxicity (11%). Tipifarnib was either reduced in dose (N=10) or discontinued (N=8) due to toxicity or non-compliance. The overall CBR is shown; should accrual continue, all 14 evaluable patients must have CB in order to meet the pre-specified efficacy objective. For the ET-resistant group, 18 were resistant to AI therapy (or AI plus tam in 5) and 2 to tam. * Number eligible/evaluable for CBR. Conclusions: The tipifarnib-fulvestrant combination is not likely to produce a CBR of at least 70%. The 45% CBR in ET-resistant disease may merit further evaluation in this setting. [Table: see text] No significant financial relationships to disclose.

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Phase II, noncomparative, open label, multicenter, study of osimertinib, in patients with locally advanced or metastatic EGFR mutated, T790M undetectable or unknown non-small cell lung cancer (Stage IIIB-IV) after no immediate prior EGFR TKI (OSIRIS study).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21116 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21116-e21116

Author(s):

Hector J. Soto Parra ◽

Laura Noto ◽

Francesco Verderame ◽

Domenico Galetta ◽

Vito Barbieri ◽

...

Keyword(s):

Phase Ii ◽

Null Hypothesis ◽

Type I Error ◽

Objective Response ◽

Locally Advanced ◽

Local Therapy ◽

Attrition Rate ◽

Type I ◽

Open Label ◽

Egfr Tki

e21116 Background: Osimertinib (OSI) is a potent irreversible EGFR TKI approved for 1st line therapy advanced EGFR+ NSCLC and for 2nd line T790M+ pts. The AURA trial showed promising results even in pts with T790M- NSCLC after no immediate prior OSI in locally advanced or metastatic EGFR+ NSCLC, T790M undetectable or unknown, after 1st line EGFR TKI and subsequent chemotherapy. Methods: This phase II trial was performed to investigate the role OSI in locally advanced or metastatic EGFR+ NSCLC, T790M undetectable or unknown, after 1st line EGFR TKI (1 or 2 generation) and subsequent chemotherapy. Eligible pts (M or F, > 18 years, ECOG 0-2) received OSI (80 mg/day) until disease progression or unacceptable toxicity. Objective response rate (ORR) was the primary endopoint. Assuming a 10% attrition rate, 90 pts were planned to be enrolled according to the Optimal Simon’s 2 stage design. In the first stage, 32 pts were planned to be accrued, and if ≤ 3 responses were observed the study would be stopped. Otherwise, 49 additional pts were planned to be accrued. The null hypothesis would have been rejected if ≥ 12 responses were observed. This design yields a type I error rate of 0.05 and 80% power. Results: From May 2017 to October 2020, a total of 54 pts were enrolled (17 M and 37 F, mean age 66 years). The study was stopped early due to an extremely slow enrolment rate. However, the ORR of 31.5% (95% CI 19.5% - 45.5%) was significantly higher than the null hypothesis of 9% (p<0.0001). 17 pts obtained a partial response and 20 a stable disease with an overall disease control rate of 68.5%. Median PFS was 9 mos and median OS was 15 mos. Forty-one pts experienced at least 1 adverse event (51.8% treatment related), more than 90% Grade 1 or 2, the most common being diarrhea. Conclusions: Despite early termination and incomplete recruitment, the treatment with OSI in pts with undetectable or unknown T790M showed a significant ORR and a PFS in line with results in T790M+. Currently, OSI represents the preferred option in naïve pts with EGFR+ NSCLC, regardless of T790M status and for pts who progress the recommended subsequent therapies include local therapy, continuing OSI or chemotherapy; in this new scenario, our results confirm that OSI rechallenge in subsequent line after chemotherapy should be explored. This research was conducted with support from AstraZeneca. Clinical trial information: 2016-002555-17.

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Cabozantinib As Salvage Therapy for Patients With Tyrosine Kinase Inhibitor–Refractory Differentiated Thyroid Cancer: Results of a Multicenter Phase II International Thyroid Oncology Group Trial

Journal of Clinical Oncology ◽

10.1200/jco.2017.73.0226 ◽

2017 ◽

Vol 35 (29) ◽

pp. 3315-3321 ◽

Cited By ~ 39

Author(s):

Maria E. Cabanillas ◽

Jonas A. de Souza ◽

Susan Geyer ◽

Lori J. Wirth ◽

Michael E. Menefee ◽

...

Keyword(s):

Thyroid Cancer ◽

Targeted Therapy ◽

Phase Ii ◽

Differentiated Thyroid Cancer ◽

Kinase Inhibitor ◽

Objective Response ◽

Evaluation Criteria ◽

Growth Factor Receptor ◽

Progression Free Survival ◽

Multikinase Inhibitor

Purpose Sorafenib and lenvatinib are oral multikinase inhibitors targeting vascular endothelial growth factor receptor (VEGFR) and approved for radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). However, there are no approved second- or third-line therapies. MET is implicated in resistance to VEGFR inhibitors. Cabozantinib is an oral multikinase inhibitor targeting MET in addition to VEGFR and is approved for medullary thyroid cancer. In a phase I study of cabozantinib, five of eight patients with DTC previously treated with a VEGFR-targeted therapy had an objective response to cabozantinib. Patients and Methods Patients with RAI-refractory disease with Response Evaluation Criteria in Solid Tumor (RECIST) measurable disease and evidence of progression on prior VEGFR-targeted therapy were enrolled in this single-arm phase II study. The cabozantinib starting dose was 60 mg/day orally but could be escalated to 80 mg if the patient did not experience a response. Patients underwent tumor assessment according to RECIST v1.1 every 8 weeks. In this study, if at least five of 25 response-evaluable patients had an objective response, cabozantinib would be considered a promising agent in this patient population. Results Twenty-five patients were enrolled. The median age was 64 years, and 64% of patients were men. Twenty-one patients had received only one prior VEGFR-targeted therapy (sorafenib, pazopanib, or cediranib), and four patients had received two such therapies. The most common treatment-related adverse events were fatigue, weight loss, diarrhea, palmar-plantar erythrodysesthesia, and hypertension. One drug-related death was noted. Of the 25 patients, 10 (40%) had a partial response, 13 (52%) had stable disease, and two (8%) had nonevaluable disease. The median progression-free survival and overall survival were 12.7 months and 34.7 months, respectively. Conclusion Cabozantinib demonstrated clinically significant, durable objective response activity in patients with RAI-refractory DTC who experienced disease progression while taking prior VEGFR-targeted therapy.

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NCT04552223: A phase II study of nivolumab plus BMS-986016 (relatlimab) in patients with metastatic uveal melanoma (UM) (CA224-094).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps9590 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS9590-TPS9590

Author(s):

Jose Lutzky ◽

Lynn G. Feun ◽

Norma Magallanes ◽

Deukwoo Kwon ◽

J. William Harbour

Keyword(s):

T Cells ◽

Mhc Class Ii ◽

Uveal Melanoma ◽

Phase Ii ◽

Phase Ii Study ◽

Performance Status ◽

Objective Response ◽

Type I ◽

Tumor Escape ◽

Potential Candidate

TPS9590 Background: Uveal melanoma (UM) is a rare disease but 50% of patients will eventually develop metastatic disease, for which not effective therapy is available. Liver-directed therapies, immunotherapy, targeted therapy and chemotherapy have limited activity [1]. Lymphocyte activation gene 3(LAG-3) is an immune checkpoint receptor associated with decreased T-cell effector function and tumor escape. Preclinical models have shown that dual inhibition of LAG-3 and PD-1 blockade generates synergistic anti-tumor activity [2]. Recent preclinical data indicates that uveal melanoma CD8+ T cells express the checkpoint receptor LAG3 to a greater extent than PD1 or CTLA4 [3,4]. Therefore, LAG3 is a potential candidate for checkpoint inhibitor immunotherapy in UM. Relatlimab is a human LAG-3-specific antibody isolated from immunized transgenic mice which binds to a defined epitope on LAG-3 with high affinity and specificity and potently blocks the interaction of LAG-3 with its ligand, MHC Class II. Methods: This is an open-label, single arm, single site investigator-initiated phase II study, NCT04552223. Based on Simon two-stage minimax design, 13 patients will be enrolled in Stage 1. If at least one response is noted, the study will proceed to Stage 2 and enroll an additional 14 patients. The null hypothesis will be rejected if 4 or more responses are observed among 27 patients. This design achieves 5% type I error and 80% power when the true ORR is 20%. The trial opened to accrual in December 2020. As of February 15, 2021 four patients had been enrolled the first stage of accrual. Main eligibility criteria include patients with biopsy proven metastatic uveal melanoma, previously untreated with PD-1, CTLA-4 and/or LAG-3 blocking antibodies and in good performance status. Enrolled patients are treated in the outpatient setting. Nivolumab 480 mg is mixed in the same bag with relatlimab 160 mg and administered intravenously over 60 minutes every 4 weeks until disease progression or intolerable toxicity for up to 24 months. The primary endpoint is best objective response rate (ORR). Secondary endpoints include disease control rate (DCR), progression-free survival (PFS), overall survival (OS), median duration of response (mDOR), and adverse events (AEs). Correlative studies will evaluate pre- and post-treatment characteristics of T cells in the tumor microenvironment and blood. Clinical trial information: NCT04552223.

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Phase II study of binimetinib with imatinib in patients with unresectable KIT-mutant melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps9594 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS9594-TPS9594

Author(s):

Katy K. Tsai ◽

Iwei Yeh ◽

Adil Daud ◽

Ari Oglesby

Keyword(s):

Phase Ii ◽

Null Hypothesis ◽

Response Rate ◽

Phase Ii Study ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Specific Treatment ◽

Type I ◽

True Response ◽

Phase Ii Studies

TPS9594 Background: Immune checkpoint inhibitors (ICI) have transformed treatment for patients (pts) with advanced melanoma, as have BRAF/MEK inhibitors for pts with BRAF V600-mutant melanoma. However, pts with acral or mucosal melanomas are in particular need of more options given a lower objective response rate (ORR) to ICI, and lower incidence of BRAF V600 driver mutation. Such BRAF mutations are found in only 5-10% of acral/mucosal melanomas, while KIT mutations/amplifications are found in 10-20%. Even when present, a KIT alteration does not guarantee response to KIT inhibition, with only about one-third responding as previously shown in 3 phase II studies. A significant number of KIT-mutant melanomas have been shown to demonstrate NF1 or SPRED1 loss, with recent preclinical work showing that such alterations are associated with the loss of negative suppression of RAS, resulting in RAS activation and MEK dependence. We hypothesize that NF1 or SPRED1 loss cooperates with KIT mutations to drive melanomagenesis and resistance to KIT inhibition, and propose to target this vulnerability with a combination approach to targeted therapy. This phase II study will be the first to evaluate the efficacy and safety of binimetinib plus imatinib in pts with KIT-mutant melanoma. Methods: This is an investigator-initiated phase II study of binimetinib in combination with imatinib in pts with BRAF V600 WT, KIT-mutant unresectable melanoma who have progressed on or who are ineligible for ICI (NCT04598009). Pts will be ≥18 yo with performance status ECOG 0-2, and have unresectable Stage IIIB/C/D or Stage IV melanoma that is BRAF V600 WT and KIT-mutant by CLIA-certified testing platform. Pts will have progressed on prior ICI or other standard-of-care (SOC) therapies, or be ineligible for or unable to tolerate SOC therapies. Pts with brain metastasis will be eligible if clinically stable and determination made that no CNS-specific treatment is required prior to study start. Pts previously treated with a MEK inhibitor will be excluded. A Simon 2-stage Minimax design will be used; the null hypothesis that the true response rate is 0.1 will be tested against a one-sided alternative. 15 pts will be accrued in the first stage. If there are £1 responses, the study will be stopped. Otherwise, 10 additional pts will be accrued for a total of 25. The null hypothesis that the true response rate is 0.1 will be rejected if ≥6 responses are observed. This yields a type I error rate of 0.05 and power of 0.8017 when the true response rate is 0.3.Primary endpoint: ORR (RECIST). Secondary endpoints: duration of response, progression-free survival, overall survival, clinical benefit rate (CR, PR, or SD ≥16 weeks), safety profile (CTCAE). Exploratory objectives to include investigations of association between clinical response and baseline NF1 and SPRED1 status, and of pathologic correlates of acquired resistance. Study began enrolling pts in December 2020 and is ongoing. Clinical trial information: NCT04598009.

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